Dr. Wang of the Brain Research Center, National Yang-Ming University, and the Neurological Institute, Taipei Veterans General Hospital, received consulting fees from Eli Lilly, Daichi-Sankyo, and Novartis for advisory board membership and honorariums from Bayer as a moderator.

)Originally released August 17, 1995; last updated December 3, 2019; expires December 3, 2022

Substance headache is a headache that develops de novo with the use or exposure of a substance. The clinical manifestations of substance-induced headache are variable. In this article, the authors update the current evidence regarding the clinical manifestations and pathophysiology of headache associated with the acute use or exposure of certain substances, with specific focus on nitric oxide donor, and carbon monoxide and calcitonin gene-related peptide, which provides a better understanding of headache biology.

Key points

• The clinical manifestations of headache associated with the use or exposure of substances are variable.

• Headache attributed to substances is currently placed under Section 8 of the International Classification of Headache Disorders, 3rd edition (2018).

• Nitric oxide and calcitonin gene-related peptides are crucial components in the pathophysiology of primary headache disorders and they have been used to experimentally trigger headache attacks.

• Headache is the most common symptom among individuals with symptomatic carbon monoxide exposure. Headache attributed to monosodium glutamate might be associated with its dose-dependent neuronal toxicity.

• Alcohol, cocaine, and histamine can cause immediate headache after exposure and delayed headache in predisposed individuals. Subjects vulnerable to alcohol-induced migraine or cluster headache could have a genetic predisposition.

Historical note and terminology

The codification of headache diagnosis by the International Headache Society in 1988 had a considerable impact on the study and understanding of headache (Headache Classification Committee of the International Headache Society 1988). The second edition of the classification revised section 8: headache attributed to a substance or its withdrawal (Headache Classification Committee of The International Headache Society 2004). The committee took the view that if a headache develops de novo with the use of a substance, it should be coded as being secondary to that substance; however, if the sufferer has already had the headache type and it is triggered by the substance, “judgment is required,” and it may be classified as the primary headache type. In the third edition (beta version) of the International Classification of Headache Disorders, the definition was slightly modified (Headache Classification Committee of the International Headache Society 2018). When a headache occurs de novo in close temporal relation to exposure of a substance, it remains true to code, the headache as a secondary headache attributed to exposure to that substance. However, when there is a pre-existing headache with characteristics of a primary headache disorder and that headache becomes chronic or significantly worse in close temporal relation to exposure to a substance, both the initial headache diagnosis and a diagnosis of “Headache attributed to a substance” should be given.

If you are a former subscriber or have registered before, please log in first and then click select a Service Plan or contact Subscriber Services. Site license users, click the Site License Acces link on the Homepage at an authorized computer.